Volume 272, Number 21, Issue of May 23, 1997 pp. 13484-13488
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Inhibition of Protein Geranylgeranylation Causes a Superinduction of Nitric-oxide Synthase-2 by Interleukin-1 in Vascular Smooth Muscle Cells

(Received for publication, January 29, 1997, and in revised form, March 13, 1997)

Jonathan D. Finder , Jennifer L. Litz , Michelle A. Blaskovich ^§ , Terence F. McGuire ^§ , Yimin Qian ^¶ , Andrew D. Hamilton ^¶ , Paul Davies ^§ and Saïd M. Sebti ^§

From the Departments of ^§ Pharmacology,  Pediatrics, and ^¶ Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Recently, we have designed farnesyltransferase and geranylgeranyltransferase I inhibitors (FTI-277 and GGTI-298) that selectively block protein farnesylation and geranylgeranylation, respectively. In this study, we describe the opposing effects of these inhibitors on interleukin-1 (IL-1)-stimulated induction of nitric-oxide synthase-2 (NOS-2) in rat pulmonary artery smooth muscle cells (RPASMC) and rat hepatocytes. Pretreatment of cells with GGTI-298 caused a superinduction of NOS-2 by IL-1. RPASMC treated with GGTI-298 (10 µM) prior to IL-1 (10 ng/ml) expressed levels of NOS-2 protein five times higher than those exposed to IL-1 alone. This superinduction of NOS-2 protein by pretreatment with GGTI-298 resulted in nitrite concentrations in the medium that were 5-fold higher at 10 ng/ml IL-1 and 10-fold higher at 1 ng/ml IL-1. Furthermore, NOS-2 mRNA levels in RPASMC were also increased 6- and 14-fold (at 10 and 1 ng/ml IL-1, respectively) when the cells were pretreated with GGTI-298. In contrast, treatment of cells with the inhibitor of protein farnesylation, FTI-277 (10 µM), blocked IL-1-induced NOS-2 expression at mRNA and protein levels. Pretreatment with lovastatin, an inhibitor of protein prenylation, resulted in superinduction of NOS-2. This superinduction was reversed by geranylgeraniol, but not by farnesol, further confirming that inhibition of geranylgeranylation, not farnesylation, is responsible for enhanced NOS-2 expression. The results demonstrate that a farnesylated protein(s) mediates IL-1 induction of NOS-2, whereas a geranylgeranylated protein(s) represses this induction.

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